The complement system is a complex group of proteins and glycoproteins, which together play an important role in host defense against infection. Complement can be activated by three distinct pathways, the classical (antibody-dependent), the alternative and the lectin pathway. Activated complement generates pro-inflammatory peptide mediators (C3a and C5a) and a cytolytic membrane attack complex (C5b-9). By its indiscriminative nature, complement has the potential to cause significant damage to self-tissues. This is particularly true in an autoimmune disease setting where autoantibodies are produced and immune complexes are deposited in vital organs such as the kidney with subsequent activation of the classical pathway. Thus, complement activation is well established to be a major effector pathway in autoantibody-mediated inflammatory injury in immune glomerulonephritis. So far, however, the parameters that determine complement susceptibility in immune glomerulonephritis have not been clearly defined. In this project, we will address the overall hypothesis that membrane-anchored regulators of complement activation, either acting at the C3 cleavage step or at the C5b-9 assembly step, are critical parameters of complement-mediated injury in immune glomerulonephritis. Our approach is to use knockout mouse lines deficient in complement regulators and determine their susceptibility to anti-glomerulus basement membrane (GBM)-induced glomerulonephritis. Our specific aims are: (1) to test the hypothesis that mice deficient in the terminal complement regulator CD59 are more susceptible to anti-GBM glomerulonephritis; (2) To test the hypothesis that there is overlap and synergy between different complement regulators such that mice deficient in two C3 regulators (DAF and Crry), and mice deficient in a C3 regulator (DAF) and the terminal regulator (CD59) sustain more injury than mice deficient in a single regulator; (3) to test the hypothesis that the increased disease susceptibility of complement regulator-deficient mice can be ameliorated by administration of recombinant soluble C3 regulators (DAF or Crry). These studies will increase our understanding of the pathogenesis of complement-mediatedautoimmune injury and facilitate the development of complement-based therapeutic strategies.